State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Oncogene. 2013 Sep 5;32(36):4294-303. doi: 10.1038/onc.2012.432. Epub 2012 Sep 24.
MicroRNAs have key roles in tumor metastasis. Here, we describe the regulation and function of miR-34a and miR-34c (miR-34a/c) in breast cancer metastasis. Expression analysis verified that miR-34a/c expression is significantly decreased in metastatic breast cancer cells and human primary breast tumors with lymph node metastases. Overexpression of miR-34a/c could inhibit breast cancer cell migration and invasion in vitro and distal pulmonary metastasis in vivo. Further studies revealed that Fos-related antigen 1 (Fra-1 or Fosl1) is a downstream target of miR-34a/c as miR-34a/c bound directly to the 3'untranslated region of Fra-1, subsequently reducing both the mRNA and protein levels of Fra-1. Silencing of Fra-1 recapitulated the effects of miR-34a/c overexpression, whereas enforced expression of Fra-1 reverses the suppressive effects of miR-34a/c. Moreover, significant downregulation of miR-34a in metastatic breast cancer tissues was found to be inversely correlated with Fra-1 expression. Our results demonstrate that miR-34a/c functions as a metastasis suppressor to regulate breast cancer migration and invasion through targeting Fra-1 oncogene and suggest a therapeutic application of miR-34 in breast cancer.
微小 RNA 在肿瘤转移中具有关键作用。在这里，我们描述了 miR-34a 和 miR-34c（miR-34a/c）在乳腺癌转移中的调控和功能。表达分析验证了 miR-34a/c 在转移性乳腺癌细胞和具有淋巴结转移的人类原发性乳腺癌肿瘤中的表达显著降低。miR-34a/c 的过表达可以抑制乳腺癌细胞在体外的迁移和侵袭以及体内远端肺转移。进一步的研究表明，Fos 相关抗原 1（Fra-1 或 Fosl1）是 miR-34a/c 的下游靶标，因为 miR-34a/c 直接结合 Fra-1 的 3'非翻译区，随后降低 Fra-1 的 mRNA 和蛋白水平。Fra-1 的沉默再现了 miR-34a/c 过表达的效果，而 Fra-1 的强制表达则逆转了 miR-34a/c 的抑制作用。此外，在转移性乳腺癌组织中发现 miR-34a 的显著下调与 Fra-1 表达呈负相关。我们的研究结果表明，miR-34a/c 作为一种转移抑制因子，通过靶向 Fra-1 致癌基因来调节乳腺癌的迁移和侵袭，并提示 miR-34 在乳腺癌中的治疗应用。
